The station was opened as part of the original route of the Charing Cross, Euston & Hampstead Railway (now the Charing Cross branch of the Northern line) on 22 June 1907. Prior to the station's opening, the name of "Seymour Street" had been proposed. After opening, it was little used, and for many years it was open only on weekdays, and before 1966 Edgware-bound trains passed through without stopping.

The station's location on the Northern line is unusual due to the dual-branch nature of that line. On the Charing Cross branch, Mornington Crescent is between Camden Town and Euston. The City branch also runs from Camden Town to Euston, but via tunnels which take an entirely different route to the Charing Cross branch and which do not pass through Mornington Crescent. Although contemporary tube maps show Mornington Crescent to the west of the City branch tunnels, it is in fact to the east of them: the two branches cross over one another at Euston, so that between Euston and Camden Town, the City branch tunnels run to the west of the Charing Cross branch on which Mornington Crescent is situated. Harry Beck's 1933 tube map represented this correctly.

On 23 October 1992 the station was shut so that the then 85-year-old lifts could be replaced. The intention was to open it within one year. However, the state of neglect meant other work had to be completed, and the station was closed for most of the 1990s, amidst talk of it closing permanently.

However, a concerted campaign to reopen the station was launched, as the station is held in fond regard due to the popular BBC Radio 4 panel game I'm Sorry I Haven't A Clue, which frequently features the game round Mornington Crescent, a game which takes its name from the station.

During the station's rebuilding, the original distinctive light blue tiling pattern was restored to the station (though taking into account modern requirements). The ticket hall was reconstructed and the original emergency stairs closed. A second lift shaft was converted (losing the unnecessary extra two lifts) into a staircase on one side and a series of station facilities on the other.

Since its 1998 reopening, the station has been open at the same times as most other stations, including weekends, in an attempt to relieve the pressure on the increasingly busy nearby Camden Town station.

China Miéville mentions this station and its long state of disuse during the 1990s in his novel King Rat (1998), also using it as scene of a brutal murder by dismemberment via a passing train.

In The Atrocity Archives (2004) by Charles Stross, the secret main entrance to the extremely secret Government establishment (the "Laundry") which the protagonist Bob Howard works for is situated in the gentlemen's toilets of Mornington Crescent tube station.

Mornington Crescent is used by Robert Rankin in many of his novels as the home of the Ministry of Serendipity, a fictional agency whose main activity is to ensure the British Empire rules the globe, via dealings with alien activity and suchlike, the top secret nature of the ministry being the main reason why the station was only open on weekdays and closed for "repairs" for much of the 1990s.